DESCRIPTION: Sympathetic preganglionic neurons (SPNs) in the thoracolumbar spinal cord provide, via the postganglionic neurons, the sympathetic nerve innervation to smooth and myocardial muscle. The long-term goal of this project is to provide a comprehensive understanding of the spinal/supraspinal circuitry and the transmitter mechanism that regulates the activity of SPNs, which in turn contributes to the homeostasis of milieu interieur. A newly discovered peptidergic pathway that may impact upon the activity of SPNs will be the focus of this proposal. Immunohistochemical studies indicate the presence of pituitary adenylate cyclase activating polypeptide immunoreactive (PACAP-ir) fibers in the rodent IML where the majority of SPNs are located in the spinal cord. The hypothesis is that PACAP is active on SPNs and that activation of this novel peptidergic pathway affects cardiovascular activity. A multi-disciplinary approach will be used to address three issues (1) the origin of PACAP-IR fibers to the rat IML, (2) the effect of PACAP on single SPNs and on synaptic transmission, and (3) the physiological consequence of activation of PACAP receptors with respect to blood pressure and heart rate. Combined immunohistochemical and tract-tracing techniques will be used to determine the origin of PACAP-IR fibers projecting to the rat IML. Whole-cell patch recording techniques will be used to study the cellular actions of PACAP and the underlying signal transduction mechanism on SPNs in immature rat spinal cord slices. Lastly, PACAP neurons in the medulla of anesthetized rats will be activated and the resulting change in blood pressure and heart rate will be assessed. The result will provide a fundamental understanding of this new peptidergic pathway to the SPNs and the mechanisms of action of this peptide. As a similar PACAP pathway exists in the human spinal cord, information derived from this study may be applicable to human as well. Lastly, specific PACAP receptor antagonists and agonists may be targeted for new drug development in the management of cardiovascular disorders that have a neurogenic component, such as hypertension and stroke.